Process for obtaining enantiomers of cis-olirtine

ABSTRACT

The procedure comprises (a) the enantioselective reduction of a pro-chiral ketone (III) by using a reducing and agent and chiral catalyst, both boron derivatives, in an anhydrous solvent or mixture of anhydrous solvents to form an enantiomer of an alcohol (II), and (b), the alkylation of (II), in phase transfer conditions, with optionally prior isolation and purification thereof, with 2-chloro-N,N-dimethylethylamine, to form an enantiomer of (I). Cyzolirtine exhibits analgesic properties.

This application is a 371 of PCT/ES98/00223, filed Jul. 31, 1998.

DESCRIPTION

1. Field of the Invention

This invention refers to a new procedure for obtaining the enantiomersof cyzolirtine,(±)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine,that consists of a sequential process of asymmetric reduction of aketone followed by alkylation of the alcohol formed.

2. Background of the Invention

The racemic mixture(±)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine(cyzolirtine), of formula I, ##STR1## described in the European patentEP 289 380, shows analgesic properties and currently is in a phase ofclinical trials. The two enantiomers of the compound of formula (I) havebeen synthesised and their analgesic properties evaluated [J. A. Hueso,J. Berrocal, B. Gutierrez, A. J. Farre and J. Frigola, Biorg. Med. Chem.Lett. 1993, 3, 269]. It was found that the dextro-rotatory enantiomerwas the most active.

The enantiomers, whose formulae are (+)-I and (-)-I, were obtained byO-alkylation of the enantiomers of formulae (+)-II and (-)-IIrespectively, ##STR2##

The enantiomer of formula (+)-II has been obtained by synthesis withvery low yields, using (-)-ethyl madelate, allowing the absoluteconfiguration (R) to be assigned to the compound of formula (+)-II. Theenantiomers of formula II have also been obtained from laboriousprocesses of separation, by column chromatography or by fractionatedcrystallisation, of the diastereoisomeric esters formed by reaction ofthe compound of formula (+)-II with (+)-O-acetylmandelic acid. Theyields obtained were 22% for the enantiomer of formula (-)-II and 25%for the enantiomer of (+)-II [J. A: Hueso, J. Berrocal, B. Gutierrez, A.J. Farre and J. Frigola, Bioorg. Med. Chem. Lett. 1993, 3, 269].

On the other hand, during the last few years, obtaining enantiomers byasymmetric synthesis has become an important synthesis method. Theasymmetric or enantioselectivity synthesis methods are very abundant andhave been extensively described [a) for a treatment of this topic seeMorrison, Asymmetric Synthesis, 5 vols., Academic Press: New York,1983-1985. b) For books, see Nogradi, Stereoselective Synthesis, VCH:New York, 1986; Eliel, Otsuka, Asymmetric Reactions and Processes inChemistry, American Chemical Society: Washington, 1982; Morrison,Mosher, Asymmetric Organic Reactions, Prentice-Hall: Englewood Cliffs,N.J., 1971; Izumi, Tai, Stereo-Differentiating Reactions, AcademicPress: New York, 1977. c) For reviews see Ward, Chem. Soc. Rev., 1990,19, 1; Whitesell, Chem. Rev., 1989, 89, 1581; Fujita, Nagao, Adv.Heterocycl. Chem. 1989, 45, 1; Oppolzer, Tetrahedron, 1987, 43, 1969;Seebach, Imwinkelried, Weber, Mod. Synth. Methods, 1986, 4, 125;Mukaiyama, Asami, Top. Curr. Chem., 1985, 127, 133].

The enantioselective reduction of pro-chiral ketones to obtain alcoholswith a raised enantiomeric purity is currently the topic of many studiesin organic chemistry. [For reviews of the topic see: Brown, Cho, Park,Ramachandran, J Org. Chem., 1987, 52, 5406; Singh, Synthesis, 1992, 605;Brown, Ramachandran, Acc. Chem. Res., 1992, 25, 16; Midland, Morrell, inHouben-Weyl Methods of Organic Chemistry, Helmchen; Hoffmann, Mulzer,Schaumann, Eds. Thieme Verlag: Stuttgart, 1995, Vol. E21d, p4049]. Inparticular, during the last few years the use of oxazoborolidines asligands has constituted a very important advance in the asymmetricreduction of ketones. [For recent reviews see: Walbaum and Martens,Tetrahedron: Asymmetry, 1992, 3, 1475; Deloux and Srebnik, Chem. Rev.,1993, 93, 763. See also: Corey, Bakshi, Shibata, Chen, Singh, J. Am.Chem. Soc., 1987, 109, 7925; Franot, Stone, Engeli, Spondlin, Waldvogel,Tetrahedron: Asymmetry, 1995, 6, 2755 and references therein; Hong, Gao,Nie, Zepp, Tetrahedron Lett., 1994, 35, 6631; Gadja, Tetrahedron:Asymmetry, 1994, 5, 1965; Willems, Dommerholt, Hammink, Vaahost, Thijs,Zwanenburg, Tetrahedron Lett., 1995, 36, 603; Dubois, Fiaud, Kagan,Tetrahedron: Asymmetry, 1995, 6, 1097; Meier, Laux, Tetrahedron, 1996,52, 589; Schwink, Knochel, Tetrahedron Lett., 1996, 37, 25].

The use of borane as reducing agent and of a chiral1,3,2-oxazaborolidine as catalyst has been disclosed for theenantioselective reduction of prochiral ketones [EP 0 305 180 A2] aswell as for the enantioselective reduction of a-iminoketones [WO95/29146]. WO 93/23408 discloses some enantioselective oxazaborolidinecatalysts useful for the enantioselective reduction of prochiral ketonesusing a borane reducing agent. However, said documents do notspecifically disclose the enantioselective reduction of the pro-chiralketone phenyl-(1-methyl-1H-pyrazol-5-yl)ketone.

The object of the present invention consists of providing a commerciallyuseful procedure, with a suitable yield and enantiomeric purity, forseparately obtaining the dextro-rotatory enantiomer of formula (R)-(+)-Iand levo-rotatory enantiomer of formula (S)-(-)-I.

DETAILED DESCRIPTION OF THE INVENTION

The procedure to which the present invention relates is based on asequential process of asymmetric reduction of the pro-chiral ketone offormula III, ##STR3## using an optically active catalyst, to obtain anoptically active compound of formula II which, once isolated or withoutisolation, is submitted to an alkylation reaction to give rise to theformation of the optically active compound of formula (I).

The procedure object of the present invention is based on the reductionof the pro-chiral ketone of formula III to obtain the carbinol offormula II with raised enantiomerical purity and the posterioralkylation of said alcohol, previously isolated or crude (not isolated),with 2-chloro-N,N-dimethylethylamine in phase transfer conditions togive the enantiomers of cyzolirtine (+)-I and (-)-I.

Enantioselective reduction is carried out using reagents derived fromboron as reducing agents and chiral oxazaborolidines derived fromenantiomerically pure aminoalcohols, as catalysts. In particular, thereducing agents derived from boron used can be diborane, catecolborane,the complexes of boron with THF, borane-dimethylsulphide,borane-1,4oxathiane and other derivatives. The chiral ligands usedcatalytically between 1% and 50% molar, are oxazoborolidines, derivedfrom optically active aminoalcohols, such as (S)- and(R)-3,3-diphenyl-1-methylpyrrolidine[1,2-c]

Enantioselective reduction is carried out using reagents derived fromboron as reducing agents and chiral oxazaborolidines derived fromenantiomerically pure aminoalcohols, as catalysts. In particular, thereducing agents derived from boron used can be diborane, catecolborane,the complexes of boron with THF, borane-dimethylsulphide,borane-1,4-oxathiane and other derivatives. The chiral ligands usedcatalytically between 1% and 50% molar, are oxazoborolidines, derivedfrom optically active aminoalcohols, such as (S)- and(R)-3,3-diphenyl-1-methylpyrrolidine[1,2-c]-1,3,2-oxazaborole[generically known as (S)- and (R)-2-methyl-(CBS)-oxazaborolindine], andits derivatives substituted at the boron atom by alkyl groups, such as(S)- and (R)-3,3-diphenyl-1-butylpyrrolidine[1,2-c]-1,3,2-oxazaborole,or aromatic groups, such as (S)- and(R)-1,3,3-triphenylpyrrolidine[1,2-c]-1,3,2-oxazaborole, (S)- and(R)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, (4R, 5S) and (4S,5R)-5-phenyl-3,4-dimethyl-1,3,2-oxazaborolidine, (4R, 5S)- and (4S,5R)-5-phenyl-2,4-dimethyl-1,3,2-oxazaboroline, (4R, 5S)- and (4S,5R)-5-phenyl-4-methyl-1,3,2-oxazaboroline, (4R, 5S)- and (4S,5R)-5-phenyl-2-methyl-1,3,2-oxazaboroline, among others, that may becommercial, or prepared prior to the reaction or formed "in situ".

The normal procedure consists of mixing the chiral catalyst (between 1%and 50% molar with respect to the keton), the reducing agent (1-10equivalents) and the ketone of formula III in an anhydrous solvent, suchas dichloromethane, toluene, xylene, benzene, pentane, hexane, heptane,petrol ether, 1,4-thioxane, diethyl ether, diisopropyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxiethane, and in general anyaprotic anhydrous solvent susceptible to being used in a chemicalreduction process with boron derivatives, or in a mixture of theaforementioned solvents, toluene being the preferred solvent andtoluene/tetrahydrofuran the preferred mixture. Said process can becarried out at temperatures that range between -78° C. and 55° C., thepreferred temperatures lying between -18° C. and room temperature. Thereaction times vary between 2 and 24 hours.

The alcohol of formula II obtained can be isolated and purified bycolumn chromatography or by crystallisation, or it can be used withoutprior isolation, using the toluene solution obtained in the reductionprocess, for the following alkylation reaction in phase transferconditions. These conditions consist of using an aprotic solvent such astoluene along with an aqueous solution of sodium hydroxide or potassiumhydroxide and a quaternary ammonium salt as a catalyst. The mixture isstirred at a temperature between 50° C. and the reflux temperature for atime of between 2 hours and 24 hours.

By way of example, process for obtaining the enantiomers of formula Iand its corresponding citrate salts are described, either by isolatingthe intermediate optically active alcohols of formula II (method A) orwithout isolating them (method B). These examples are only presented toillustrate the procedure object of the present invention and they shouldnot be taken as limiting its scope.

EXAMPLE 1

Obtaining the citrate of(R)-(+)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine,citrate of (+)-I.

METHOD A

To a solution of(R)-3,3-diphenyl-1-methylpyrrolidine[1,2-c]-1,3,2-oxazaborole 1M intoluene (7.5 ml, 7.5 mmol) cooled to -10° C., under an argon atmosphere,a solution of catecolborane 1M in THF (100 ml, 100 mmol) is addeddropwise. To the resulting mixture a solution ofphenyl-(1-methyl-1H-pyrazol-5-yl)ketone, III (9.30 g, 50 mmol) in drytoluene is added. Once the addition has been completed the mixture isstirred for 1 hour at -10° C. and then over night at room temperature.Next, MeOH (10 ml) is carefully added while stirring, which ismaintained for 6 hours. The reaction mixture is concentrated to half thevolume, washed successively with water and with a solution of saturatedNaCl, dried and the solvent evaporated to yield an oil which is purifiedon a silicagel column, eluted with a mixture of ethyl acetate: petrolether (7:3) to give (R)-(+)-phenyl-(1-methyl-1H-pyrazol-5-yl)methanol,(+)-II (7.82 g, 83%), whose optical purity as determined by chiral HPLCis 99%. M.p. 81-83° C.; [α]_(D) =+16.6 (c=1.0, CHCl₃).

Next a mixture of carbinol (+)-II (7.44 g, 40 mmol) dissolved in toluene(80 ml), NaOH 40% (40 ml), tetrabutylamonium bromide (1 g) and2-chloro-N,N-dimethylethylamine chlorohydrate (11.52 g, 80 mmol) is keptat reflux temperature for 7 hours. The mixture is cooled, the organiclayer separated, and the mixture repeatedly washed with water, dried andevaporated to give(R)-(+)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine,(+)-I (9.53 g, 92%). The product obtained is dissolved in ethanol andtreated with citric acid monohydrate, crystallising the correspondingcitrate of (+)-I (15.42 g) with an optical purity of 99.1%, asdetermined by chiral HPLC. M.p.129-130° C.; [α]_(D) =+12.3 (c=1.0,CHCl₃).

METHOD B

To a solution of(R)-3,3-diphenyl-1-methylpyrrolidine[1,2-c]-1,3,2-oxazaborole 1M intoluene (120 ml, 0.12 mmol) cooled to 0° C., under an argon atmosphere,a solution of borane-dimethylsulphide 2M in toluene (800 ml, 1.6 mol) isadded dropwise. To the resulting mixture a solution ofphenyl-(1-methyl-1H-pyrazol-5-yl)ketone, III (148.8 g, 0.8 mmol) in drytoluene (1000 ml) is added. Once the addition has been completed themixture is stirred for 1 hour at 0° C. and 5 hours at room temperature.Next, MeOH (200 ml) is carefully added and stirring maintained for 6hours. The reaction mixture is concentrated to half the volume, washedsuccessively with water, a solution of 1M citric acid (2×50 ml) and asaturated solution of NaCl, and dried. The resulting toluene solution isused in the continuation of the synthesis without posteriorpurification.

Next, a mixture of the toluene solution from the previous step (1600ml), NaOH 40% (800 ml), tetrabutylamonium bromide (16 g) and2-chloro-N,N-dimethylethylamine chlorohydrate (184.3 g, 1.6 mmol) iskept at reflux temperature for 7 hours. The mixture is cooled, theorganic layer separated, and the mixture repeatedly washed with water,dried and evaporated to give(R)-(+)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine,(+)-I (174.1 g, 84% overall). The product obtained is dissolved inethanol and treated with citric acid monohydrate, crystallising thecorresponding citrate of (+)-I (284.2 g) with an optical purity of91.9%, as determined by chiral HPLC. M.p.129-131° C.; [α]_(D) =+11.6(c=1.0, CHCl₃).

EXAMPLE 2

Obtaining the citrate of(S)-(+)-2-[Phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine,citrate of (-)-I.

METHOD A

Following a procedure analogous to method A of example 1, from(S)-3,3-diphenyl-1-methylpyrrolidine[1,2-c]-1,3,2-oxazaborole 1M intoluene (1.5 ml, 1.5 mmol), catecolborane 1M in THF (20 ml, 20 mmol) andphenyl-(1-methyl-1H-pyrazol-5-yl)ketone, III (1.86 g, 10 mmol),(S)-(-)-phenyl-(1-methyl-1H-pyrazol-5-yl)methanol, (-)-II (1.58 g, 84%)is obtained, whose optical purity as determined by chiral HPLC is 98.9%.M.p.: 80-83° C.; [α]_(D) =-16.2 (c=1.0, CHCl₃). Said carbinol (1.50 g)is alkylated by means of a phase transfer process analogous to thatdescribed earlier, then treated with citric acid and re-crystallised inethanol to give the citrate of(S)-(-)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine,(-)-I (3.27 g, 91%) with an optical purity of 99%, as determined bychiral HPLC. M.p.: 129-131° C.; [α]_(D) =-12.2 (c=1.0, CHCl₃).

METHOD B

Following a procedure analogous to method A of example 1, from(S)-1,3,3-diphenyl-1-methylpyrrolidine[1,2-c]-1,3,2-oxazaborole 1M intoluene (120 ml, 0.12 mmol), borane-dimethylsulphide 2M in in toluene(20 ml, 40 mmol) and phenyl-(1-methyl-1H-pyrazol-5-yl)ketone, III (3.72g, 20 mmol) a crude carbinol is obtained dissolved in toluene, which isalkylated without posterior purification by means of a phase transferprocess analogous to that described earlier, then treated with citricacid and re-crystallised in ethanol to obtain the citrate of(S)-(-)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine,with an optical purity of 92%, as determined by chiral HPLC. M.p.: 128

What is claimed is:
 1. A procedure for obtaining the enantiomers ofcyzolirtine,(±)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine,of formula I, ##STR4## that comprises the enantioselective reduction ofthe pro-chiral ketone of formula III ##STR5## using a borane reducingagent and a chiral catalyst derived from boron selected from a chiraloxazaborolidine, in an anhydrous solvent or mixture of anhydroussolvents at temperatures lying between -78° C. and 55° C., to form anenantiomer of the alcohol of formula II, ##STR6## and the alkylation, inphase transfer conditions, of this optically active compound, prior toisolation and purification or without isolation, with2-chloro-N,N-dimethylethylamine.
 2. A procedure, according to claim 1,that consists of performing the asymmetric reduction of the pro-chiralketone phenyl-(1-methyl-1H-pyrazol-5-yl)ketone of formula III, to giverise to the formation of an enantiomer of formula II, usingcatecolborane as the reducing agent.
 3. A procedure, according to claim1, that consists of performing the asymmetric reduction of thepro-chiral ketone phenyl-(1-methyl-1H-pyrazol-5-yl)ketone of formulaIII, to give rise to the formation of an enantiomer of formula II, usingborane-dimethylsulphide as the reducing agent.
 4. A procedure, accordingto claim 1, that consists of performing the asymmetric reduction of thepro-chiral ketone phenyl-(1-methyl-1H-pyrazol-5-yl)ketone of formulaIII, to give rise to the formation of an enantiomer of formula II, using(R)-(+)-3,3-diphenyl-1-methylpyrrolidine[1,2-c]-1,3,2-oxazoborole as acatalyst.
 5. A procedure, according to claim 1, that consists ofperforming the asymmetric reduction of the pro-chiral ketonephenyl-(1-methyl-1H-pyrazol-5-yl)ketone of formula III, to give rise tothe formation of an enantiomer of formula II, using(S)-(-)-3,3-diphenyl-1-methylpyrrolidine[1,2-c]-1,3,2-oxazoborole as acatalyst.
 6. A procedure, according to claim 1, that consists ofperforming the asymmetric reduction of the pro-chiralphenyl-(1-methyl-1H-pirazol-5-yl)ketone of formula III, obtaining,isolating and purifying an enantiomer of formula II.
 7. A procedure,according to claim 6, that consists of performing the asymmetricreduction of the pro-chiral phenyl-(1-methyl-1H-pirazol-5-yl)ketone offormula III, obtaining, isolating and purifying the enantiomer(R)-(+)-phenyl(1-methyl-1H-pyrazol-5-yl)methanol, (+)-II.
 8. Aprocedure, according to claim 6, that consists of performing theasymmetric reduction of the pro-chiralphenyl-(1-methyl-1H-pirazol-5-yl)ketone of formula III, obtaining,isolating and purifying the enantiomer(S)-(-)-phenyl(1-methyl-1H-pyrazol-5-yl)methanol, (-)-II.
 9. Aprocedure, according to claim 1, that consists of performing theasymmetric reduction of the pro-chiral ketone chiralphenyl-(1-methyl-1H-pirazol-5-yl)ketone of formula III, and withoutisolating the enantiomer formed, reacting it with2-chloro-N,N-dimethylethylamine to obtain an enantiomer of cyzolirtine,of formula I.
 10. A procedure, according to claim 9, that consists ofperforming the asymmetric reduction of the pro-chiral ketone chiralphenyl-(1-methyl-1H-pirazol-5-yl)ketone of formula III, and withoutisolating the enantiomer formed, reacting it with2-chloro-N,N-dimethylethylamine to obtain the enantiomer(R)-(+)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine,(+)-I.
 11. A procedure, according to claim 9, that consists ofperforming the asymmetric reduction of the pro-chiral ketone chiralphenyl-(1-methyl-1H-pirazol-5-yl)ketone of formula III, and withoutisolating the enantiomer formed, reacting it with2-chloro-N,N-dimethylethylamine to obtain the enantiomer(S)-(-)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine,(-)-I.
 12. A procedure, according to claim 1, that consists ofperforming the asymmetric reduction of the pro-chiral ketone chiralphenyl-(1-methyl-1H-pirazol-5-yl)ketone of formula III, in an anhydroussolvent or a mixture of anhydrous solvents.
 13. A procedure, accordingto claim 12, that consists of performing the asymmetric reduction of thepro-chiral ketone chiral phenyl-(1-methyl-1H-pirazol-5-yl)ketone offormula III, in toluene or a mixture of toluene and tetrahydrofuran. 14.A procedure, according to claim 1, that consists of performing theasymmetric reduction of the pro-chiral chiralphenyl-(1-methyl-1H-pirazol-5-yl)ketone of formula III, at temperatureslying between -18° C. and room temperature.